Methods of preventing the development of mucositis and related disorders

Abstract

Disclosed is a method of preventing the development of mucositis in a subject undergoing radiation therapy or chemotherapy for a disease in need thereof comprising administering an effective amount of a mammalian target of rapamycin (mTOR) inhibitor, such as rapamycin, to the subject. Further disclosed is a method of increasing the lifespan of a normal oral keratinocyte and/or reducing oxidative stress in a normal epithelial cell, wherein the method comprises administering an effective amount of an mTOR inhibitor to a subject undergoing radiation therapy or chemotherapy for a disease in need thereof.

1 . A method of preventing the development of mucositis in a subject undergoing radiation therapy or chemotherapy for a disease in need thereof comprising administering an effective amount of a mammalian target of rapamycin (mTOR) inhibitor to the subject. 
     
     
         2 . A method of preventing hair loss in a subject undergoing radiation therapy or chemotherapy for a disease in need thereof comprising administering an effective amount of a mammalian target of rapamycin (mTOR) inhibitor to the subject. 
     
     
         3 . A method of increasing the lifespan of a normal oral keratinocyte in a subject undergoing radiation therapy or chemotherapy for a disease in need thereof comprising administering an effective amount of a mammalian target of rapamycin (mTOR) inhibitor to the subject. 
     
     
         4 . The method of  claim 1 , wherein epithelial progenitor cells are preserved after radiation therapy relative to their condition prior to radiation therapy or chemotherapy. 
     
     
         5 . The method of  claim 3 , wherein the disappearance of the epithelial progenitor marker p63 is decreased. 
     
     
         6 . The method of  claim 3 , wherein the level of mitochondrial superoxide dismutase (MnSOD) is increased in the normal oral keratinocyte upon administration of mTOR inhibitor compared to the level of MnSOD in the absence of mTOR inhibitor. 
     
     
         7 . A method of reducing oxidative stress in a normal epithelial cell compared to a cancerous epithelial cell in a subject undergoing radiation therapy or chemotherapy for a disease in need thereof comprising administering an effective amount of a mammalian target of rapamycin (mTOR) inhibitor to the subject. 
     
     
         8 . The method of  claim 7 , wherein the normal and cancerous epithelial cells are from an oral mucosa. 
     
     
         9 . The method of  claim 7 , wherein the amount of reactive oxygen species (ROS) is reduced in a normal epithelial cell compared to a cancerous epithelial cell. 
     
     
         10 . The method of  claim 1 , wherein the disease is cancer. 
     
     
         11 . The method of  claim 10 , wherein the cancer is head and neck squamous cell carcinoma (HNSCC) or cancer of the tongue. 
     
     
         12 . The method of  claim 10 , wherein the cancer is an oral cancer. 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 1 , wherein the mTOR inhibitor is selected from the group consisting of rapamycin, prodrugs of rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, 32-deoxorapamycin, 16-pent-2-ynyloxy-32-deoxorapamycin, 16-pent-2-ynyloxy-32 (S or R)-dihydro-rapamycin, 16-pent-2-ynyloxy-32 (S or R)-dihydro-40-O-(2-hydroxyethyl)-rapamycin, 40-[3-hydroxy-2-(hydroxy-methyl)-2-methylpropanoate]-rapamycin (CCI779), 40-epi-(tetrazolyl)-rapamycin (ABT578), 42-O-(2-hydroxy)ethyl rapamycin (RAD001), AP23573, TAFA-93, and biolimus. 
     
     
         15 . The method of  claim 14 , wherein the mTOR inhibitor is selected from rapamycin, AP23573, RAD001, CCI779, and TAFA-93. 
     
     
         16 . The method of  claim 15 , wherein the mTOR inhibitor is rapamycin. 
     
     
         17 . The method of  claim 1 , wherein the mTOR inhibitor is orally administered. 
     
     
         18 . The method of  claim 2 , wherein the mTOR inhibitor is selected from the group consisting of rapamycin, prodrugs of rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, 32-deoxorapamycin, 16-pent-2-ynyloxy-32-deoxorapamycin, 16-pent-2-ynyloxy-32 (S or R)-dihydro-rapamycin, 16-pent-2-ynyloxy-32 (S or R)-dihydro-40-O-(2-hydroxyethyl)-rapamycin, 40-[3-hydroxy-2-(hydroxy-methyl)-2-methylpropanoatel-rapamycin (CCI779), 40-epi-(tetrazolyl)-rapamycin (ABT578), 42-O-(2-hydroxy)ethyl rapamycin (RAD001), AP23573, TAFA-93, and biolimus. 
     
     
         19 . The method of  claim 3 , wherein the mTOR inhibitor is selected from the group consisting of rapamycin, prodrugs of rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, 32-deoxorapamycin, 16-pent-2-ynyloxy-32-deoxorapamycin, 16-pent-2-ynyloxy-32 (S or R)-dihydro-rapamycin, 16-pent-2-ynyloxy-32 (S or R)-dihydro-40-O-(2-hydroxyethyl)-rapamycin, 40-[3-hydroxy-2-(hydroxy-methyl)-2-methylpropanoatel-rapamycin (CCI779), 40-epi-(tetrazolyl)-rapamycin (ABT578), 42-O-(2-hydroxy)ethyl rapamycin (RAD001), AP23573, TAFA-93, and biolimus. 
     
     
         20 . The method of  claim 7 , wherein the mTOR inhibitor is selected from the group consisting of rapamycin, prodrugs of rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, 32-deoxorapamycin, 16-pent-2-ynyloxy-32-deoxorapamycin, 16-pent-2-ynyloxy-32 (S or R)-dihydro-rapamycin, 16-pent-2-ynyloxy-32 (S or R)-dihydro-40-O-(2-hydroxyethyl)-rapamycin, 40-[3-hydroxy-2-(hydroxy-methyl)-2-methylpropanoatel-rapamycin (CCI779), 40-epi-(tetrazolyl)-rapamycin (ABT578), 42-O-(2-hydroxy)ethyl rapamycin (RAD001), AP23573, TAFA-93, and biolimus. 
     
     
         21 . The method of  claim 2 , wherein the disease is cancer.